Hydrogel Drug Delivery Systems

Chapter TwoGASTRORETENTIVE DOSAGE FORMSthe formulation will remain in the stomach for prolonged periods, releasing the drug in situ, which will then dissolve in the liquid contents and slowly pass into the small intestineUnlike a conventional extended-release dosage form, which gradually releases the drug during transit along the gastrointestinal tract, such a delivery system would overcome the problems of drugs that are absorbed preferentially from specific sites within the gastrointestinal tract.DELAYED -RELEASE DOSAGE FORMSIn contrast to extended-release dosage forms, which release drug over a prolonged period of time, delayed-release formulations release a bolus of drug after a predetermined time or in a predetermined location. In practice, there are two types of delayed-release formulations designed either to target release to the proximal small intestine (enteric coating) or the colon.ENTERIC COATINGcommonly used to prevent release of a gastric-irritant or acid-labile drug molecule in the stomach.by coating the dosage form with a polymer, that remains intact in the stomach while breaking down at the more neutral pHs encountered in the small intestineshellac, gelatin, and keratinA polymer with a dissolution threshold pH in the range 5 to 6 is considered ideal for use as an enteric coat; this is based on the pH of the stomach, rarely reach this levelA lag time of 1.5 to 2 h postgastric emptying for complete disintegration of an enteric-coated capsule and tabletmodified-release dosage forms should be designed as multiple-unit systems, in which the increased surface-area-to-volume ratio would reduce the time for intestinal disintegration while minimizing the possibility of total failure of the dosage form and premature release in the stomach

COLONIC DRUG DELIVERYpH-Responsive Drug DeliverypH-sensitive polymers with a dissolution threshold pH in the range 6.8 to 7.5pH of the terminal ileum is typically around 1 to 2 pH units higher thanthat in the cecum , because of the cecal fermentation of dietary fiber to fattypH-sensitive coating would begin to destabilize in the region of the terminal ileum or cecum, minimizing absorption from the small intestine and facilitating delivery of therapeutic agent to the colonThe limitations inter- and intraindividual variation in gastrointestinal transit times and pHTime-Responsive DeliveryTime has been utilized on the assumption that the small-intestinal transit time is relatively constant, in comparison to gastric emptying and colonic residence time, at 3 to 5 hThe lag time preceding drug release can be controlled by altering the composition of the hydrogel plug, but a lag time of 5 h is considered appropriate for colon arrivalVariable release positions and poor spreading of capsule contents have been reported, limiting the effectivenessPressure-Responsive DeliveryA pressure-controlled colon delivery capsule (PCDC) has been described, which utilizes the increase in pressure of the luminal contents to effect drug release.The device comprises the drug, dispersed in a suppository base, coated with the hydrophobic polymer ethylcelluloseThe suppository base melts after the PCDC has been swallowed, resulting in the capsule resembling a liquid-filled ethylcellulose balloon, that is capable of remaining intact in the small bowel but which will rupture when exposed to the more intense haustral contractions and luminal contents of higher viscosity encountered in the colon.

Bacteria-Responsive DeliveryThe bacterial count in the colon is approximately 10 million times higher than that in the proximal gastrointestinal tractAzo-polymers being selectively degraded by bacterial enzymes present in the large bowel and known to be potential carcinogens a variety of naturally occurring polysaccharides have been exploited as alternative bacterial responsive polymers as they are generally regarded as safe (GRAS)Hydrogel Drug DeliverySystemsHYDRO GELS IN DRUG DELIVERYHydrogels are three-dimensional networks of hydrophilic polymer chains that do not dissolve but can swell in waterThe high biocompatibility of hydrogels results from their high water content and soft-surface propertiesIn addition, hydrogels are versatile materials because they can be tailor-made to possess various properties by manipulating the synthetic or processing methods. The physicochemical, mechanical, and biological properties, as well as new functional properties, can be easily modulated. For example, hydrogels can be made to respond to environmental stimuli, such as temperature, pH, light, and specific molecules.DEFINITIONS AND CLASSIFICATIONS

Natural polymers, such as proteins, polysaccharides, and DNA, can be cross-linked to form hydrogels but is not easySynthetic hydrogels can be easily prepared by cross-linking polymerization of synthetic monomersWhen the polymer chains of a hydrogel are connected by covalent cross-linking, they are known as chemical gelsBecause the polymer chains are covalently linked to each other, hydrogels cannot be reshaped once set. For this reason, chemically cross-linked hydrogels are also called thermoset hydrogelPhysical gels are defined as continuous, disordered, three-dimensional networks formed by associative forces capable of forming noncovalent cross-linksSuch noncovalent cross-links include hydrogen bonding, hydrophobic interaction, stereocomplex formation, ionic complexation, and crystallinity.As noncovalent associations are reversible, physical hydrogels can be processed by solvent casting or heating, therefore they are also referred to as thermoplastic hydrogels

Hydrogels with interconnected pores provide unique properties of fast-swelling kinetics and high swelling ratios. Porous hydrogels can be prepared by a variety of methods, such as the porosigen technique, phase separation technique, cross-linking of individual hydrogel particles, andgas-blowing (or foaming) techniqueDepending on the pore size, porous hydrogels are divided into microporous (10 to 100 nm range), macroporous (100 nm to 10 m range)superporous hydrogels (10 to 1000 m range)

PROPERTIES AND STRUCTURES OF HYDROGELSThe swelling property is usually characterized by measuring their capacity to absorb water or aqueous solutionsThe swelling ratio (Rs)=(WsWd)/Wd where Ws and Wd are the weights of swollen and dried hydrogels, respectivelyThe swelling properties are determined by many factors, including the type and composition of monomers, cross-linking density, and other environmental factors such as temperature, pH, and ionic strength.The swelling force is counterbalanced by the retractive force induced by the cross-links of the networkThe cross-linking density and the swelling property are inversely related

The cross-linking density of a hydrogel is also closely related to other important properties such as mechanical strength and permeability.The mechanical properties of hydrogels basically depend on their composition and structureBecause of the high water content of fully swollen hydrogels, they are, in general, mechanically very weak. The low mechanical strength can be improved by increasing the cross-linking density, making an interpenetrating network (IPN) structure or copolymerization with hydrophobic comonomers. These approaches are usually accompanied by the decreased swelling property.Biodegradable hydrogels that can slowly degrade and disappear from the body have attracted significant attention for drug deliver applications. The degradation mechanism is also used to control the kinetics of drug release from the hydrogel formulations. Biodegradation occurs by either simple hydrolysis or enzyme-catalyzed hydrolysis.A large number of biodegradable polymers, such as poly(lactic acid) (PLA), poly(glycolic acid) (PGA), poly(lacticco-glycolic acid) (PLGA), poly(-caprolactone), poly(ortho esters), polyanhydrides, and polyphosphoesterMany of the biodegradable polymers are hydrophobic and water insoluble, thus they cannot be directly used to make hydrogels. combined with hydrophilic polymers, to give significant swelling behavior in aqueous environmentsHYDROGEL FABRICATIONS

SSHSSSSSSSSSSHSHSHSHSHSHSHSHPolymerThiomerCOOSHCOO--COO-SHSHCa2+/Me2+pH7-9COOCOOMe2+--COOCOOMe2+SHSH--BASIC CONCEPTS OF HYDROGEL DRUG DELIVERYThe benefits of controlled drug delivery are: (1) more effective therapies with reduced side effects, (2) the maintenance of effective drug concentration levels in the blood, (3) patients convenience as medicines are taken less frequently, (4) increased patient complianceRelease of drug molecules from a delivery device is controlled by diffusion, dissolution, osmosis, and ion exchange.Diffusion controlled drug deliverydrugs are loaded in the water-insoluble polymer matrices (monolithic devices) or in reservoirs that are subsequently covered with a water-insoluble polymer membrane (reservoir devices)Osmosis-controlled drug delivery systemsthe core of the devices is often made of hydrogels as a source of osmotic pressureIon-exchange-based drug delivery systemswater-soluble polyelectrolytes are highly crosslinked, and these are basically hydrogels with very high cross-linking densities, which prevents the system from swelling.

ENVIRONMENT-SENSITIVE HYDROGELSHydrogels can be prepared to possess the properties that can respond to environmental changes, such as temperature, pH, light, and specific molecules such as glucose or more commonly intelligent or smart hydrogels.

oxidationextracellulare milieuThiomerpDNAnanoparticlesIntracellulare, reducing milieuGSH content 1-10 mM

Temperature-sensitive hydrogels poly(N-isopropylacrylamide) (PNIPAAm)The water solubility of PNIPAAm and its copolymers is dramatically changed around their lower critical solution temperature (LCSTs), which can be modulated to be close to the body temperatureIt is soluble in water when the temperature is lower than the LCST, but becomes insoluble above the LCSTAt lower temperatures, hydrogen bonding between hydrophilic groups of the polymer chains and water molecules is dominant, resulting in higher water solubility or higher swellingAs the temperature increases, hydrophobic interactions among hydrophobic groups become stronger, resulting in shrinking of the hydrogels because of interpolymer chain association through hydrophobic interactions.This property has been used for on/off drug delivery systemsswelling at low temperature and shrinking at high temperature.

pH-sensitive hydrogelspH-sensitive hydrogels containing acidic or basic pendant groups, which can accept or donate protons upon environmental pH changes.Cationic polimer (poly(N,N-diethylaminoethyl methacrylate) dissolve or swell at low pH because of ionizationpH-sensitive hydrogels swell at low pH and shrink at hight pH (cation polimers)pH-sensitive hydrogels swell at high pH and shrink at low pH (anion polimers)dissolve or swell at low pH because of ionization The pH difference between the stomach and the intestine is large enough to be of use in the case of pH-sensitive hydrogels.Drug release can be accelerated when the device reaches the intestine, where pH is near neutral. This type of hydrogel is useful for protecting acid-labile drugs in the stomach.

glucose-sensitive hydrogelsself-regulated insulin deliver systemsThe most common method involves adding glucose oxidase to pH-sensitive hydrogelsglucose is converted to gluconic acid by glucose oxidase in the hydrogels, and the resulting pH decrease can induce the swelling of the pH-sensitive hydrogels to release more insulin

Concanavalin A (ConA) is also frequently used for modulated insulin delivery.ConA is a glucose-binding protein obtained from a plant. In ConA-based systems, insulin can be modified with glucose for interaction with ConA for modulated release in the presence of free glucose ConA is used as a physical cross-linker of glucose-attached polymer chains.BIODEGRADABLE HYDROGELSBiodegradable hydrogels can be broken down into biologically acceptable low-molecular-weight molecules in the body by simple hydrolysis or enzymatic catalysisBiodegradable hydrogels can have many advantages in drug delivery, such as improved biocompatibility and flexibility in controlling the release of drugsColon-specific hydrogels were developed by using polymers that can be degraded by microbial enzymes in the colonSPECIFIC APPLICATIONS OF HYDROGELS IN ORAL DRUG DELIVERY

HYDROTROPIC HYDROGELS FOR DELIVERY OF POORLY SOLUBLE DRUGSmany drugs have been found to be poorly soluble in water, resulting in low absorption and low bioavailabilityLow-molecular-weight hydrotropes have been used to increase the aqueous solubility of poorly soluble drugsAs the concentrations of hydrotropes used in the delivery of poorly soluble drugs are very high, there is an unfavorable absorption of significant amounts of hydrotropes by the body. To prevent the undesirable coabsorption of hydrotropes, polymeric forms of hydrotropes were developedThe study showed that the cross-linked hydrotropic polymers (e.g., hydrotropic hydrogels) maintained the hydrotropic property. Paclitaxel solubility in hydrotropic hydrogels (e.g., hydrogels of poly(2-(4-vinylbenzyloxy)-N-picolylnicotinamide) was 5000 times higher than the paclitaxel solubility in pure waterThank You